The intracellular free Ca2+ concentration of CMS neurons is highly regulated. Small changes in the cytosolic Ca2+ concentration and different patterns of Ca2+ transients are used by CMS neurons to mediate important functional and developmental processes. Increases in the cytosolic Ca2+ concentration can arise from entry of extracellular Ca2+ through ion channels in the plasma membrane or via the release of Ca2+ from intracellular stores. Both entry of extracellular Ca2+ and release of Ca2* from intracellular stores are directly coupled to neuronal function. For the development of acute and chronic degenerative diseases reducing the viability and function of CNS neurons several studies indicate that both changes in intracellular second messenger concentration and pathological increases in the intracellular Ca2+ concentration promote pathogenesis. The present application will test the two-pronged hypothesis that Ca2+ signaling of CNS neurons is functionally regulated by associated proteins of intracellular Ca2+ channels and that control of their expression and function represents a novel target for CNS neuroprotection. The proposed experiments designed to test this hypothesis will investigate the functional mechanism underlying this interaction under experimentally induced disease conditions in models of acute and chronic degenerative CNS diseases. The specific aims of this proposal are to determine a) changes in the expression and localization, b) function and c) modulation of these proteins based on therapeutic intervention studies in pre-clinical models of AD and age-related cognitive impairment. The overall goal of the study is to identify a novel mechanism of neuroprotection and determine its potential as a strategy for neuroprotective therapies targeting the aging brain and age-related neurodegenerative diseases such as Alzheimer's disease. This therapy approach will have the potential to be both preventative and therapeutic in nature and to complement existing treatment designs and rationales. Thus, potential new targets for treating those devastating conditions affecting the aging population may be identified.